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High dose interleukin-2 (Aldesleukin) - expert
consensus on best management practices-2014
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Janice P Dutcher1Email author,
Douglas J Schwartzentruber2,
Howard L Kaufman3,
Sanjiv S Agarwala4,
Ahmad A Tarhini5,
James N Lowder6 and
Michael B Atkins7
Journal for ImmunoTherapy of Cancer20142:26
DOI: 10.1186/s40425-014-0026-0
© Dutcher et al.; licensee BioMed Central Ltd. 2014
Received: 25 April 2014
Accepted: 16 July 2014
Published: 16 September 2014
Abstract
Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors
that could produce complete responses (CRs) that were often durable for decades without further
therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and
metastatic melanoma (mM) could probably be classified as "cures". Recent publications have
suggested improved efficacy, perhaps due to improved patient selection based on a better
understanding of clinical features predicting outcomes. Guidelines for clinical management were
established from experience at the National Cancer Institute (NCI) and an affiliation of institutions
known as the Cytokine Working Group (CWG), who were among the first to utilize HD IL-2
treatment outside of the NCI. As new centers have opened, further management variations have
emerged based upon center-specific experience, to optimize administration of IL-2 and provide high
quality care for patients at each individual site. Twenty years of evolution in differing environments
has led to a plethora of clinical experience and effective management approaches. The goal of this
review is to summarize the spectrum of HD IL-2 treatment approaches, describing various effective
strategies that incorporate newer adjunctive treatments for managing the side effects of IL-2 in
patients with mRCC and mM. The goal for IL-2 therapy is typically to administer the maximum
number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible
toxicity. This review is based upon a consensus meeting and includes guidelines on pre-treatment
screening, criteria for administration and withholding doses, and defines consensus criteria for safe
administration and toxicity management. The somewhat heterogeneous best practices of 2014 will
be compared and contrasted with the guidelines provided in 2001 and the package inserts from 1992
and 1998.
Keywords
Interleukin-2 Clinical management Cytokines Renal cell carcinoma Melanoma Treatment guidelines
Introduction
Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors
that could produce complete responses (CRs) that were often durable for decades without further
therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and
metastatic melanoma (mM) could probably be classified as "cures". Despite this remarkable
response quality in a small minority of patients, the requirement for hospitalization at expert
immunotherapy centers to manage the side effects of high dose IL-2 (HD IL-2) administration has
limited its utilization. Early studies evaluated high dose IL-2 in comparison with lower doses both in
mRCC and mM in an effort to minimize toxicity. However the data demonstrated superiority of the
high dose (HD) regimens in both diseases [1]-[4]. Faced with the task of administering of HD IL-2,
guidelines for clinical management were established from experience at the National Cancer
Institute (NCI) [5]-[7]. An affiliation of institutions known as the Cytokine Working Group (CWG),
who were among the first to utilize HD IL-2 treatment outside of the NCI, led the implementation of
management strategies in new settings [8]. Currently there are more than 60 centers in North
America administering HD IL-2 for mRCC and mM. As new centers have opened, further
management variations have emerged, based upon center-specific experience, to optimize
administration of IL-2 and provide high quality care for patients at each individual site. Twenty
years of evolution in differing environments has led to a plethora of clinical experience and effective
management approaches.
Recent publications have suggested improved efficacy, perhaps due to improved patient selection
based on a better understanding of clinical features predicting outcomes [9]-[11]. At the same time,
the number of doses of IL-2 being administered per course has decreased, reducing toxicity without
an apparent impact on efficacy [1],[2],[7]-[10],[12]-[14]. These trials have stipulated the standard
dose and schedule of HD IL-2, but this delivery and management could vary according to each site's
tolerance for specific toxicities and approach to managing them. Virtually no information exists in
the literature regarding the specifics of administration practices or median doses per cycle given at
major HD IL-2 centers.
In recent years, new therapies have been approved in both mRCC and mM. Prior treatment with
these new agents may influence the eligibility of patients for HD IL-2, modify their response, or
change the management strategies of HD IL-2. In many instances, little information exists in the
literature regarding the integration of HD IL-2 therapy with other treatments and more guidance
would be desirable.
The goal of this review is to summarize the spectrum of HD IL-2 treatment approaches, describing
various effective strategies that incorporate newer adjunctive treatments for managing the side
effects of IL-2 in patients with mRCC and mM. The goal for IL-2 therapy is typically to administer
the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe,
irreversible toxicity. This review is based upon a consensus meeting and includes guidelines on pretreatment screening, criteria for administration and withholding doses, and defines consensus criteria
for safe administration and toxicity management. The somewhat heterogeneous best practices of
2014 will be compared and contrasted with the guidelines provided in 2001 and the package inserts
from 1992 and 1998.
Early physiology investigations of high dose IL-2 therapy
In the 1980's and 1990's, clinical trials evaluating the efficacy of HD IL-2 yielded a great deal of
information on the physiologic effects of exogenous, HD recombinant IL-2 administration in
humans [15]-[27]. Early clinical studies employed IL-2 often in combination with adoptively
transferred lymphocytes referred to as Lymphokine Activated Killer (LAK) cells. In these studies, it
was not possible to separate the contribution of each modality in terms of clinical response and
emergence of treatment-related adverse events. Further complicating the picture was the fact that the
dose and schedule of IL-2 administration often varied from study to study. Although the specific
molecular and cellular mechanisms of IL-2-mediated response and toxicity are not completely
defined, IL-2 is known to result in a cascade of cytokines released at supraphysiologic levels in the
body from IL-2-activated cells. This can result in a well-described capillary leak syndrome and
eventual end-organ dysfunction [15]-[27]. The hallmarks of this "cytokine storm", are remarkably
similar to the shock syndrome associated with bacterial septicemia, and include: sustained
hypotension, tachycardia and increased vascular permeability. In addition, high serum cytokine
levels appear to be directly or indirectly toxic to the cells of multiple organs [28],[29]. Early animal
and human studies suggested a dose-response effect on both efficacy and toxicity [15]-[17]. Thus
most of the early literature described alternative methods of managing these patients than those used
for sepsis, as the desirable therapeutic effects were thought to be linked to the toxicity (5-8,24-27)
and the inciting factor (IL-2 administration) was within the physician's control.
Studies of cardiovascular physiology evaluated the universal hypotension associated with HD IL-2
administration and demonstrated high cardiac output and reduced peripheral vascular resistance
(42% mean decrease) and a decline in mean cardiac ejection fraction from between 58% to 52%
[24]-[26]. Six of ten patients in one study in which patients received HD IL-2 alone, had reductions
in their LVEF of 5% (absolute number) or greater. In a smaller study where patients were also
administered LAK cells, mean ejection fraction fell from 58 to 36%. An increase in ejection fraction
would be expected with the increased inotropy and decreased afterload associated with hypotension.
These studies suggested that HD IL-2 administration and the associated high serum levels of other
cytokines, produced toxic effects on the myocardium which are worsened by the co-administration
of LAK cells. Based upon temporal correlation of levels, TNF-α, may be the central cytokine in this
response [27]. Both studies demonstrated complete recovery of all parameters, even at 14 days,
following IL-2 administration cessation.
Renal dysfunction was virtually always reversible, and was evaluated as being both pre-renal and
renal in origin [30]-[32]. The sustained hypotension certainly reduces renal blood flow and results in
a pre-renal dysfunction characterized by high aldosterone and renin, and high tubular recovery of
sodium. Patients receiving HD IL-2 may become severely oliguric and even anuric, but rarely
manifest acute tubular necrosis, as might be expected with purely hypotensive effects. The falling
BUN:creatinine ratio and decreased filtration fraction speaks to an intrinsic renal defect probably
mediated by a downstream cytokine. The minimal proteinuria suggests that the increased vascular
permeability seen in the rest of the body is not active at the glomerular level. The rapid and
complete recovery suggests that no real structural damage occurs during IL-2 treatment.
Infections were a frequent cause of adverse events and even death in early trials of HD IL-2. The
majority of these infections were related to intravenous catheters, largely with gram positive
bacteria. These were attributed to the use of central venous multiport catheters necessary to
administer high rates of fluids or vasopressor medication [33],[34]. Aseptically-placed catheters
developed infections much earlier than would have been predicted. A granulocyte migration defect
observed in patients receiving HD IL-2 was postulated to have permitted local infections to become
systemic [33]. The use of prophylactic antibiotics, fresh placement and removal of intravenous
catheters with each cycle of treatment have largely addressed this issue [6],[7].
Making standard recommendations regarding the amount of HD IL-2 administration is complicated,
as IL-2 is typically delivered as an intravenous bolus with a fixed dose based on individual patient
weight (typically either 600,000 or 720,000 Units/kg) and then that dose delivered every 8 hours up
to a maximum of 14-15 doses subject to toxicity. Most patients receive one course of treatment that
consists of two cycles separated by a 9-14 day holiday before re-staging. The first cycle of each
course has been associated with more doses than the second in the vast majority of individuals.
Comparing total dosing is also confounded by the dropout of non-responders after the first course.
Studies do not report dosing in any routine fashion making comparisons difficult. Evolution of
management during the first decade of treatment with HD IL-2 at the NCI resulted in a 58%
reduction in number of doses in the first cycle of IL-2, with a concomitant significant reduction in
grade 3 or 4 toxicity (reduction in diarrhea by 80%, reduction in neurotoxicity by 50%, reduction in
serious pulmonary toxicity by 75%, and reduction in mortality to zero) [7]. An average of 8 x
720,000 IU/kg (equivalent to about 9 600,000 IU doses) was established for the first cycle at the
NCI. Although no statistically significant difference in the CR rate or response duration for either
mRCC or mM patients was associated with these changes some early studies showed correlation of
response with the number of doses [1],[7],[35]. Studies in the succeeding decades by the CWG, have
shown a modest decrease in the number of doses administered during the first course, from a mean
of 22 in the 1980's-early 1990's, [3] to a mean of 19 in studies published in early 2000's, [2] to 16-20
doses in most recent studies [9],[10],[13]. Variations in response rate are within the bounds expected
from relatively small trials, [9],[10],[13] and an acceptable level of grade 4 toxicity has been
achieved without sacrificing efficacy [9],[10],[13]. All recent studies demonstrate rapid reversibility
of all expected IL-2 related toxicities.
Review: Where is high dose IL-2 management today?
Screening of patients has changed as medical practice and technology has changed. Management of
cardiovascular disease is dramatically different now than 25 years ago. Physiologic age is
recognized as more important than chronological age. Prior therapy in patients encompasses many
more options, some of which may influence eligibility for and tolerability of HD IL-2. Current
approaches to toxicity management are more variable, but largely with the same technology. The
same fluids and vasopressors are used for the management of hypotension. Advances in anti-nausea
agents have improved this aspect of care. The site in the hospital where IL-2 is administered (ICU vs
step down unit, vs regular inpatient ward) and the aggressiveness in the number of doses per cycle
are highly variable from site to site. Different parameters for screening and management are utilized
according the experience and comfort of the site personnel. The tables in this paper show
recommended ranges for continuous variables and variations in management beyond the typical
approach.
Screening (Table 1)
Table 1
Pre screening recommendations for high dose IL-2 therapy
Package insert
guidelines
Disease
MM or mRCC
PS
0-1
All patients
Current best practices
MM: cutaneous better than mucosal/ocular mRCC:
clear cell/mixed histology
0-1
Under 40-50 without history
Selective testing only
Over 40-50 or prior history
EKG stress test-normal (off beta blockers)
Cardiac
function
Thallium stress testnormal
CAD corrected > 6-12 months
EKG stress test, EF, motility-normal
Cardiology consult
Prior TKI
3 month gap if possible
EKG stress test, EF, motility-normal
Abnormal stress test
Package insert
guidelines
Current best practices
Cardiology consultation
All patients
Pulmonary
function
PFTs with ABGs
Under 40-50 without history
Selective testing only
Over 40-50 or with history of smoking or pulmonary
disease
FEV1 ≥ 75% predicted
Negative MRI
No untreated CNS
Brain metastasis
metastasis
Positive MRI
Treated, asymptomatic, off steroids
Infection
Renal function
No active infections
No active infections
All patients
Serum creatinine ≤ 1.5 mg/dL
Serum creatinine ≤
1.5 mg/dL
Serum creatinine 1.5-2.0 mg/dL
All patients
Bilirubin ≤ 2.0 mg/dL
Creatinine clearance > 60 ml/min
Platelet count > 100,000
Laboratory
Hemoglobin ≥ 9.0 g/100 ml
Values within normal
limits
ANC ≥ 1500/mm3
SGOT < 3x ULN
Thyroid function normal
Other
No steroids, autoimmune disease, allografts
Substantial changes in the supportive and interventional management of disease as well as
diagnostic technology have occurred during the past 3 decades. In addition, new therapies have
become available whose chronic toxicity may impact a patient's ability to receive HD IL-2
subsequently. HD IL-2 package insert instructions are based upon literature and experience
generated during the 1980's and 1990's. What was viewed as an absolute contraindication to therapy
or a screening necessity in the past may not be sensible in today's environment. Nonetheless, careful
attention to screening of patients prior to IL-2 treatment remains critical to successful and safe
administration of this treatment. Patients with eligibility concerns should always be evaluated by the
relevant subspecialist prior to therapy and ideally followed by that physician during therapy. Less
experienced sites, however, should always err on the side of more conservative screening.
The single most important parameter for screening is a patient's functional - or performance - status,
as measured by the ECOG or Karnofsky score as this predicts likelihood of response, as well as,
tolerance of the therapy. Only patients with intact (ECOG = 0 or K = 100) or minimally impaired
(ECOG = 1 or K = 80-90) function are candidates for HD IL-2. Functionality represents an excellent
sum of the patient's total organ and physical reserve which will be severely taxed during therapy.
Secondly, the histologic and molecular subtypes of RCC and melanoma have led to more stringent
selection by histology (see variations on disease type in Table 1) based on likelihood of response to
IL-2 therapy [36].
Cardiovascular
Although cardiac toxicity remains a major concern in HD IL2 treatment, the baseline risk has
diminished in the general population in recent decades. The reduction in cigarette smoking,
aggressive prophylaxis with statin drugs and management of hypertension and cardiovascular
disease has significantly reduced the incidence of occult cardiac disease. The use of coronary artery
bypass grafts and stents has corrected existing CAD with preservation of cardiac functional reserve.
Careful attention to family history, risk factors and lifestyle is important in determining the extent of
cardiac risk and degree of screening needed in preparation for HDIL2 treatment. Although the
package insert mandates thallium screening in all patients, most sites follow different approaches, as
the thallium stress test produces many false positive results. Patients below the age of 40-50 without
relevant history or risk factors generally may not require extensive screening. Additionally, patients
with prior history of coronary artery disease which has been corrected may be considered for
treatment if this occurred at least 6-12 months in the past, but should be tested [37],[38]. The
extensive use of VEGF targeted tyrosine kinase inhibitors in mRCC is an important historical issue.
These agents can be cardiotoxic and can produce reductions in left ventricle ejection fraction,
particularly if treatment duration has exceeded one year. Ideally, patients should be off anti-vascular
endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR TKIs) for 3 months
before HD IL-2 [39]. Careful and complete screening is mandatory in these patients. An EKG
exercise treadmill stress testing is the standard modality for testing patients. Ultrasound assessment
of ejection fraction and myocardial wall activity are valuable parts of the stress test and may be
employed in patients with risk factors. Ideally, stress testing should be done with the patient off of
beta blockers, as they will be discontinued during HD IL-2 therapy. Dipyridamole (Persantin®)
stress testing may be used in patients unable to effectively use a treadmill. If the stress test is
abnormal, a cardiologist should be consulted, and ultimately determine both the need for and the
path of further evaluation to help make a final decision about eligibility.
Pulmonary
Due to pulmonary fluid overload and the demand on the myocardium caused by hypotension,
adequate oxygenation of the blood may be an issue. Smoking history and careful attention to
diseases compromising pulmonary function are important signs of reduced pulmonary reserve.
Restrictive lung disease may be debilitating during the stress of therapy. Patients without relevant
history below the age of 40-50 do not require screening unless there are risk factors or signs or
symptoms of underlying pulmonary dysfunction. An FEV1 > 75% of predicted is adequate for
predicting IL-2 tolerability. Any other tests should be ordered at the discretion of a pulmonary
consultant. Pulmonary function studies may also be useful for defining the patient's baseline
pulmonary function, which can help in management of changes observed during treatment.
Brain metastasis
Good quality magnetic resonance imaging of the brain should be obtained prior to starting HD IL-2.
Patients with brain metastases were often considered not to be candidates, however, with the advent
of stereotactic radiotherapy, an asymptomatic patient with adequately treated isolated brain
metastases and off systemic corticosteroids can be considered for treatment. Similarly, patients with
small untreated brain metastases that are limited in number and causing minimal or no edema may
be considered for IL-2 treatment [40].
Effusions
Patients with large pleural effusions or large amounts of abdominal ascites are not good candidates
for HD IL-2. The fluid shifts experienced during IL-2 treatment generally results in expansion of
existing fluid collections and will likely result in exacerbation of symptoms that will preclude
effective therapy with IL-2.
Infections
All patients should be carefully screened for infection prior to IL-2 treatment and any active
infection should be fully treated and the patient should be off antibiotics prior to starting a cycle of
HD IL-2. This includes clearance of C. difficile if that has been identified. In addition, tumor related
impingement on structures which might lead to closed space or obstructive infections should be
carefully evaluated and corrected if necessary.
Other
Most other parameters are assessed according to laboratory values which are listed in Table 1.
In the hands of experienced therapy teams, treatment can be customized with a sense of the patient's
physiologic reserve. This will help to guide the setting of the target blood pressure, the need for
specialist support and the threshold for stopping and holding doses of IL-2.
Site of administration unit
HD IL-2 administration requires trained experienced staff and an inpatient location where cardiac
and O2 saturation monitoring are available and vasopressor agents such as dopamine and
phenylephrine can be administered according to hospital policy. In addition, a low nurse to patient
ratio is necessary. These requirements are fulfilled in specialized oncology floors, transplantation
units, intensive care step down units or intensive care units in various institutions. Novice sites
might be advised to treat up to 10 patients in an intensive care setting until they are comfortable,
then move to a less intensive and expensive setting, provided there is sufficient clinical support. If
intensive care nurses or physicians are involved, they should be carefully trained in how to care for
the HD IL2 patients, as management is often counterintuitive to the management of the usual
intensive care patient. Transfer of patients from one setting to another is to be avoided if at all
possible as nursing continuity is critical [41]. If patients being managed outside the ICU develop
problems that cannot be managed safely in the current location (e.g. cardiac arrhythmia, respiratory
failure, bacterial sepsis) such patients should be promptly transported to an ICU and further IL-2
treatment stopped.
Overall schedule and dose
Most centers continue to utilize the original empirically defined NCI schedule of one week on (cycle
1), one week off, one week on (cycle 2), defined as one "course" of treatment. The inter-cycle time
may be extended by another week based upon patient recovery or site preference. The disease
response, assessed at 6-12 weeks from therapy initiation, after a full course of therapy helps
determine the value of administering another course. Any response is generally viewed as a reason
to give another course. If stable disease is observed, delay of an additional 4-6 weeks or longer
followed by reassessment may inform the decision for further dosing. Continued disease stability
over months in a patient with clearly progressive disease before therapy is frequently, although not
always, viewed as reason to continue treating. Of note, in one study, 90% of patients that achieved a
response to treatment, did so after one course of IL-2 [42]. In light of these observations, decisions
about additional courses of IL-2 should be individualized based on toxicity of prior therapy, extent
of residual disease and availability of alternative treatment options. The interval between courses
may vary considerably for a variety of other reasons including patient recovery and logistics. The
standard dose of HD IL-2 remains 600,000 IU/kg (based on initial studies), although higher and
lower approaches have been described in the literature [1]-[13],[43]. The NCI and some sites use
720,000 IU/kg [1]. For the most part, doses are given as a short bolus infusion (over 15 minutes)
every 8 hours, over the course of 5 days. Toxicities generally occur over the 6 hours following a
bolus dose, abating before the next scheduled dose. If recovery from the previous dose is not noted
at 8 hours, some centers skip a dose and resume the 8 hour schedule. Some sites extend the time
between doses to 12 hour intervals at this juncture. Individual dose reductions should not be used.
Treatment extends for 5 days, stopping when the 14th planned dose would have been administered
(end of day 5) regardless of the number of doses administered. Treatment is typically concluded
earlier when adverse events occur that make further dosing intolerable, thus only a small minority of
patients receive all 14 doses. The IL-2 treating physician will decide when to hold or stop dosing
during a cycle based upon criteria to be discussed later in this paper. The current total mean number
of doses administered is in the range of 16-20 of the 28 maximum doses in the two cycles of
treatment.
Some institutions have adopted schedules that continue to use the standard amount of IL-2 per dose
but offer variations in dosing interval and number of dosing cycles [12],[44]. These approaches
indicate that interest remains in optimizing IL-2 therapy in ways which maintain efficacy but
improve the safety profile for patients. Little data exists on the dose response curve, however, the
response rate between 600,000 or 720,000 IU/kg (HD) and 72,000 IU/kg (moderate dose) is
significantly different [1].
Initial admission and management - standing orders (Additional file 1)
Most centers have a set of routine IL-2 orders that establish the basic procedural approach of the
local IL-2 team. Although these vary considerably from site to site, they are strictly adhered to
within a site, in order to maintain continuity among nursing shifts and facilitate clinical decision
making. Standard protocols for maintaining intravenous access catheters, intravenous fluids,
prophylactic-and as needed (PRN) medications for symptom control, monitoring parameters, and
daily laboratory evaluations, guide the daily management of patients. Reactive management of
expected complications, such as hypotension, decline in oxygen saturation, tachycardia, and
alterations mental status should also be listed. Threshold values for various monitoring parameters
should be listed which require contacting the physician. Standing order specifics are imbedded in
Table 2. Additional file 1 provides an example of standing orders. These parameters take into
consideration the standards in each clinical unit, the type of monitoring available and the
philosophical approach of the team. The frequency of blood testing is usually once daily, with
additional testing as needed and directed by the IL-2 physician. Patients are admitted to the hospital
the evening before or the morning of the first IL-2 infusion. The most common dosing schedule is 8
AM, 4 AM and midnight often with the first dose being administered at 4 AM on day 1.
Table 2
Clinical management recommendations for HD IL-2 therapy
Issue
Venous access
Considerations
Management
Central line (for possible
vasopressors)
Typical
Double or triple lumen
PICC line placement
Power inject and large volume
capacity
Remove temporary lines at end
of cycle
Minimize catheter associated
infection
Variations
Broviac/Hickman catheter
Subclavian/IJ catheter
Maintenance of volume with CLS Typical
IV fluids
Boluses for blood pressure
support
D5NS or D5LR 10 ml - 125
ml/hr
Administration of drugs
PRN KCL, HCO3, Mg
replacement
Replacement of electrolytes
IL-2 only compatible with D5W
No active infections
Prevention
Infections
Chills/rigors
Fever
IV catheter likeliest source
Variations
D5W, NS, 0.45% NaCl
Typical
Gram + prophylactic antibiotic
Avoid unnecessary in-dwelling
catheters
Variations
Expanded coverage per
hospital
Chills and rigors occur 1-2 hrs
after IL-2
Fever-Typical
Prophylaxis
Acetaminophen 650 mg 30
Fever is common 2-4 hrs after IL- min pre-dose, q 4-6 hrs and
prn
2
Indomethacin 25 mg q 6-8 hrs
Fever-Variation
Naproxen
Ibuprofen
Constitutional symptoms
Muscle joint aches continuous and Chills-Typical
progressive during IL-2 treatment
Meperidine 25 mg IV q 15 m
prn
Morphine 2-4 mg IV q 15 m
prn
Nausea/vomiting
Episodic occurrence throughout
therapy
Typical- Prophylaxis
Nausea > vomiting
Ondansetron 0.15 mg/kg q 8
hrs
Issue
Considerations
Management
Variations
Granisetron 1 mg daily
Ondansetron at longer interval
Compazine 10 mg po q 6 hrs
Use of antinausea agents prn
Epigastric distress
Gastritis induced by stress,
medications
Mucositis/stomatitis
Progressive with continued
treatment
Typical
H2 blocker prophylaxis
Variation
PPI prophylaxis
Typical
No prophylaxis
Oncology mouthwash
Can be profuse and increases with
Typical
therapy
Diarrhea
5HT-3 antagonist anti-emetic
prophylaxis
Imodium
may have positively impacted
Lomotil
Narcotic
Break between IL-2 doses
Variations
5HT-3 antagonist prophylaxis
Patient monitoring
I & O, Weight
Per shift and daily
Blood pressure, pulse,
respirations, temp
Q 2-4 hrs
Blood work
Daily
EKG
Continuous cardiac monitoring
O2 Saturation
Q 2-4 hrs
Mental status examination
Aldesleukin/Interleukin-2
dose and administration
Q 8 hrs
Increase frequency as needed
IL-2 incompatible with salt
solutions.
Typical: 600,000 IU/kg
infused over 15 minutes Q 8
hrs up to 14 doses.
Dissolve in sterile water for
injection Dilute into 50 cc D5W
Variations: 720,000 IU/kg Q
8 hrs Q 12 hrs < 14 maximum
doses
Stop infusion, flush IV tubing
with 50 cc D5W before and after
each dose.
Issue
Considerations
Management
Maintain systolic BP 80-90 mm
hg
Fluid boluses, 250-500 ml NS
2xday
Blood pressure nadirs 4-6 hrs after Increase maintenance fluid rate
each dose with diminished
Phenylephrine 0.1-4.0
recovery with cumulative dosing mcg/kg/min
Hypotension
Hold next dose
DC IL-2
Prior to each dose anticipate
ability to respond to next nadir
Variations:
Dopamine 1-6 ug/kg/min
Progressive refractoriness to
support measures
Pressors with minimal fluids
Fluids without pressors
Sinus tachycardia
Common and progresses over a
cycle
Peaks 2-4 hrs after dose with fever
and hypotension
Manage BP and fever
Must resolve prior to next dose
Cardiac arrhythmias
Supraventricular tachycardia,
atrial fibrillation
Medical Conversion
Less common
Cardizem as needed
Atrial fibrillation
Digoxin
Medical Conversion
Ventricular tachycardia
Acute treatment
Discontinue IL-2
Typical
Oliguria
Output less than 50-100 cc/8
hrs Fluid bolus, if no
improvement next shift hold
IL-2 dose
Creatinine >3-4
Renal function
Rising creatinine
Stop NSAIDS and nephrotoxic
antiobiotics
Urine output and creatinine
resolve after discontinuation of
IL-2
Hold overnight dose
If only one kidney always
consider obstruction of ureter
Variations
Dopamine 1-6 mcg/kg/min
If am creatinine improved
continue
Issue
Considerations
Management
Furosemide
Tachypnea/Dyspnea
Diagnose etiology and treat
Hypoxic causes-Fluid overload,
capillary leak, bronchospasm
Pulmonary
Non hypoxic causes
Anxiety, fever, acidosis
Typical
Oxygen 2-4 L nasal cannula,
increasing up to 35%
rebreather
Reassurance or sedative for
anxiety, treat bronchospasm or
acidosis if appropriate
Hold IL-2 dose if O2sat < 95%
Variation
Maintain O 2 sat > 92-5%
Furosemide
Bronchodilators
Monitor bicarbonate
Peripheral edema
Expect to gain 5-10% body
weight
Elevation, compression, limit
fluid support in subsequent
cycles
Treat edema symptomatically
Diuretics upon conclusion of
IL-2 dosing are not necessary
but may speed process
Entrapment of peripheral nerves
in upper extremity may need
therapy
Treat peripheral nerve pain
Protean manifestations
Neurotoxicity
Typical
Formal neuro checks
Gradual onset with sudden
worsening near end of cycle
Enlist family evaluation
May persist after cessation of
therapy
Lorazepam and Haloperidol
Delusions, Visual hallucinations
Hold IL-2 liberally for
suspected neurotoxicity
Warn patient of vivid dreams
after discharge
Typical
Dermatologic
Rash, erythema, dry desquamation
Emollient lotions and creams
Oatmeal bath
Pruritus
Antihistamines
Moist dermatitis
Hold IL-2 dose
Variations
Issue
Considerations
Management
Crisco
Gabapentin
Naloxone
Narcotics
Nonalcohol, no steroid
topicals
Hypomagnesemia, hypocalcemia
(but low albumin - so corrected
may be WNL), Hypokalemia-
Daily electrolyte panels
Acidosis due to diarrhea,
hypoperfusion
Correct electrolytes cautiously
prn
Magnesium and HCO3,
particularly if diarrhea a
problem
Metabolic
Hypothyroidism a slow onset
problem
HCO3 < 18 meq/L hold dose
of IL-2
Check TSH at beginning of
cycle
RL as support fluids may
decrease need for HCO3
Hepatic
↑Bilirubin (up to 10)
Monitor daily
↓Albumin (down to 1.8)
No intervention except if
SGOT SGPT are >5x
↑Hepatic aminotransferases
Resolves spontaneously
Stop acetaminophen if
bilirubin > 5
Hematologic
↓Platelets
Transfuse platelets if < 20 K
Lymphs ↓during IL-2, ↑post
therapy
Other abnormalities require no
intervention
Eosinophils progressively ↑with Significant anemia needs
several cycles
evaluation for cause
Endocrine
Hypothyroidism - slow onset after Check TFTs at beginning of
completion of treatment
cycle and monitor TFTs with
subsequent visits
Requires serial monitoring
Toxicity management by organ system - typical management and variations (Table
2)
The most important skill in managing an HD IL-2 patient is to understand when to withhold the next
dose. Acute inter-dose exacerbations peak around 4-6 hours following each dose. Before another
dose is given, patients should be approaching or have returned to their target baselines for heart rate,
oxygen saturation and blood pressure. There should be capacity to provide increased blood pressure
and oxygenation support during the inter-dose exacerbation which will follow administration of the
next dose. Toxicities are generally cumulative, worsening and becoming refractory to management
with successive doses during the week. Preparing patients and family to expect symptoms will
alleviate their fears and enlist their support.
Fever/chills
These are the first side effects encountered by patients and can be quite disconcerting. Almost all
patients have fever with at least the first IL-2 dose, despite premedication, usually within 30-60
minutes after the dose. Over the week, these symptoms generally lessen with subsequent doses. Both
acetaminophen and non-steroidal anti-inflammatory agents (NSAIDS) are administered
prophylactically and as needed for fever. Continuous NSAIDS are not a problem despite a rising
creatinine, in view of the universal reversibility of the renal adverse events seen with IL-2.
However, holding or withdrawing NSAIDS later in the course when the creatinine rises above 3-4
mg/dL is prudent.
Often fever comes after an episode of severe chills or rigors. Significant rigors are effectively
managed by giving parenteral opioids immediately at the onset of the rigor. Although meperidine is
the most commonly used agent, morphine is also used and may be less emetogenic. Fevers and
chills which occur outside the 2-6 hour window after a dose of IL-2 must be considered as
potentially due to infection and evaluated accordingly.
Hypotension
This is the most common and important toxicity of HD IL-2 treatment (70% of patients in early
studies), reflecting capillary leak, decreased peripheral vascular resistance with high cardiac output,
characteristic of systemic inflammatory response syndrome (SIRS). A variety of causes of gap
junctional instability in endothelial cells have been postulated as the underlying mechanism for the
leak. The relationship of capillary leak to the hypotension is uncertain as changes in peripheral
vascular resistance may produce decreases in blood pressure even in the absence of capillary leak.
Hypotension is largely unavoidable and may be viewed as a clinic-dynamic parameter for drug
administration. Standing orders should specify a new baseline tolerable systolic blood pressure of at
least 20 points lower than baseline was prior to initiating IL-2. In addition, a wide pulse pressure
should be expected from a decrease in diastolic pressure. The baseline values should be customized
for each patient taking into account the individual's cardiac status and prior exposure to tyrosine
kinase inhibitors directed at the vascular endothelial growth factor pathway. During treatment this
level of hypotension becomes the new baseline that is the goal for the entire dosing period.
Typically, the acceptable target systolic pressure is about 80-90 mmHg for patients without cardiac
risk factors, but may be adjusted upward in patients who are at higher risk of coronary or cerebral
artery disease. Management of blood pressure also requires maintaining an acceptable heart rate
which will be discussed later.
The management of hypotension also appears to have the broadest spectrum of practice among
centers. The approaches hinge on a preference for using fluids versus vasopressors to maintain blood
pressure (BP). Some centers rely solely on large volumes of saline, lactated ringers or hetastarch to
maintain blood pressure with the expectation that the patient will gain at least a kilogram or more
per day, with a total weight gain of 5-10% of their body weight during the week of administration.
The relative values of colloids vs. crystalloids have been studied extensively in intensive care
situations with no obvious advantages, except for cost [45]. Fluids are administered as continuous
infusion or as boluses, in response to hypotensive episodes. Initial maintenance rates vary between
of 5-125 ml/hour. Bolus sizes vary from 100 ml to 500 ml. Since patients can experience flash
pulmonary edema, fluids should be administered cautiously during active IL-2 treatment. Other
centers will start a vasopressor, particularly dopamine or phenylephrine, immediately and more
sparingly employ maintenance and bolus fluids [46]. Patients with a history of hypertension
admitted for HD IL-2 therapy should have outpatient antihypertensive medications discontinued
immediately prior to IL-2 therapy.
Examples
Center A routinely administers HD IL-2 on the oncology unit. They utilize maintenance fluids of
75-100 ml/hour. For hypotension, patients are initially given 250-500 ml of saline, LR or hetastarch
with a second bolus of 250 ml allowed to raise the BP to the target systolic pressure. Dopamine is
used on the oncology unit if dose-limiting renal dysfunction is experienced, but no other
vasopressors, and it is used at renal doses (1-5 ug/kg/min). If a patient develops significant
tachycardia while on dopamine (greater than 120- 130/min sustained), they hold IL-2, correct
intravascular hypovolemia and allow the patient to recover. If the patient becomes fluid overloaded
with respiratory symptoms, they hold or stop IL-2, and use diuretics as necessary, prior to
respiratory compromise. The goal is to administer up to14 doses/cycle if dosing criteria are met
before each dose.
Figure 1 shows a patient with a target systolic BP of 90 experiencing BP reductions with tachycardia
3-4 hours after doses 5 and 6 of IL-2. These episodes responded promptly to a 500 ml bolus of
saline.
Figure 1
Timing of the administration of the 4th and 5th IV boluses of IL-2 is plotted versus systolic
and diastolic blood pressure and heart rate. This patient shows characteristic exacerbation of
hypertension 3-4 hours after infusion responsive to fluid boluses.
Center B treats patients in the ICU in order to maintain a lower nurse to patient ratio and permit the
use of vasopressors. Patients are given maintenance fluids of 10 ml/hour unless they have excessive
nausea/vomiting or diarrhea, in which case it is raised to 30-50 ml/hour. Volume boluses are used as
previously described for episodes of hypotension. If this does not reverse the hypotension, then
patients are started on phenylephrine at 50 micrograms/minute (0.1-2.0 ug/kg/min), titrated as
necessary to maintain BP, with a preset maximum dose level individualized per patient cardiac risk
factors between doses. The phenylephrine must be tapered back to baseline of 50
micrograms/minute or less before another IL-2 dose is given. With subsequent IL-2 doses, up to 2
fluid boluses per 8 hours may be administered for hypotension if there are no signs of pulmonary
compromise or excessive (>5% baseline weight) fluid overload, but vasopressors are the mainstay of
managing hypotension in this setting. The need for a 3rd bolus in 24 hours generally requires
holding the next dose of IL-2. Some patients become refractory to phenylephrine and require
dopamine or norepinephrine (Levophedâ„¢). Even with this regimen, patients usually gain 10-20
pounds of water weight during a 5 day course of treatment.
Figure 2 shows the course of a patient responding minimally to a bolus of saline after suffering
hypotension and tachycardia after dose 6 of IL-2. Phenylephrine is started at 50 mcg/kg/min with
return of BP and HR to acceptable levels. After the next dose hypotension and tachycardia recur and
respond minimally to an increase in phenylephrine dose and better to an additional bolus of saline.
Figure 2
Timing of the administration of the 6th and 7th IV boluses of IL-2 is plotted versus systolic
and diastolic blood pressure and heart rate. This patient is unresponsive to a fluid bolus and
phenylephrine is begun at 50 mcg per minute with good effects permitting administration of the 7th
dose. The resulting hypotension and tachycardia are treated with an increase in the phenylephrine
dose and another bolus of fluid. The late night dose will likely be held.
Experienced centers use phenylephrine and dopamine on an oncology or stem cell transplant unit,
which has the nursing staff trained to support such use and also have cardiac monitoring capability.
Their management practice is similar to that described in Center B. In any scenario, the blood
pressure/heart rate must recover to a predefined baseline prior to administering the next dose of IL2.
Cardiac arrhythmias
There is fairly uniform practice with respect to managing cardiac arrhythmias with serious
arrhythmias being uncommon. Sinus tachycardia is to be expected and a new baseline acceptable
heart rate of less than 100 beats per minute is generally recorded in the standing orders along with a
directive against the use of beta blockers. The rate typically increases after each IL-2 dose, peaks at
2-4 hours and returns to baseline prior to the next dose. It is a compensatory response to
hypotension, but is also a consequence of secondary cytokine and stress related epinephrine release
and fever. It is important to distinguish the cause in order to avoid unnecessary fluid boluses. The
tachycardia seems to become more pronounced and prolonged with an increased number of doses. It
usually resolves over time between doses and is back to baseline before the next dose. Some centers
extend the time between doses to allow recovery and others hold a dose until the next scheduled
administration time.
Isolated premature ventricular contractions (PVCs) are not a contraindication to continued IL-2
dosing, but if the frequency increases (above 10/min), or patterns such as quadrigeminy or couplets
or greater arise, holding IL-2 doses until recovery may be necessary. Less common cardiac
arrhythmias requiring immediate intervention include supraventricular tachycardia with rapid
response, atrial fibrillation with rapid response, and ventricular tachycardia. Patients may continue
IL-2, if SVT or atrial fibrillation are converted/controlled, sinus rhythm is maintained or heart rate is
controlled and there are no signs of cardiac damage. Ventricular tachycardia requires evaluation for
cardiac damage and is an absolute contraindication to more IL-2. Rarely, evidence of myocarditis or
pericarditis is noted clinically or on an EKG. This may reflect lymphocytic infiltration [25],[26]. If
concerns exist regarding myocarditis or ischemia, then cardiac enzymes or troponin should be
monitored at least daily and IL-2 discontinued if confirmed.
Dyspnea/Hypoxia
Management of dyspnea requires astute assessment and medical judgment as to causality. HD IL-2related respiratory symptoms may develop in relation to local capillary leak or lymphocyte
adherence to pulmonary vasculature or generalized fluid overload. However, patients with a
smoking history, chronic obstructive lung disease or a history of asthma may have pulmonary
symptoms related to bronchospasm, even without significant fluid overload. All of the preceding
problems will be associated with decreased oxygen saturation. The treatment will vary according to
the specifics. In addition, these patients may be febrile, uncomfortable and anxious and may be
tachypneic on that basis without associated hypoxia. Finally, an important metabolic cause of nonhypoxic tachypnea is acidosis.
The frequency of these problems varies, and is related to the center's plan for management of
hypotension - aggressive fluid resuscitation versus less fluid and early use of vasopressors. Diuretics
are used by some sites, but not recommended by most. The adverse effects on blood pressure and
kidney refractoriness within 4 hours of a recent IL-2 dose, make this a relatively futile and
counterproductive measure. Hypoxia should be quickly treated with nasal cannula oxygen, with
increased support as necessary to maintain oxygen saturation at 95%. In the context of hypotension
with an increased demand on the myocardium, adequate oxygenation is critical and patients should
not be maintained with suboptimal saturation waiting for recovery. Patients with obstructive
pulmonary disease may benefit from regular nebulizer treatments with bronchodilators, and often
they are able to continue IL-2. Elevation of the patient's bed is helpful. Performance of a chest
radiograph should be reserved for patients with clinical indications for investigation.
Oliguria/Rising creatinine
Renal toxicity is believed to be related to a hypotension-induced pre-renal component as well as an
intrinsic renal component mediated by secondary cytokines [29]-[31]. Most HD IL-2 physicians
agree that renal toxicity is a universally reversible acute toxicity without chronic effects. It is
manifest by oliguria and rising blood urea nitrogen and serum creatinine (Figure 3). All centers
agree that renal toxicity reverses very quickly, even after withholding one dose of IL-2. All centers
monitor renal function and urine output, but use quite different criteria for holding doses and
different thresholds for concern. Criteria vary from minimum concern for a rising creatinine and a
threshold of <100 ml/day urine output to creatinine thresholds of 2.5 and 10-15 ml of urine per hour,
managed on a per shift schedule by fluid boluses. The typical range of serum creatinine considered
for concern is from 3.0 to 5.0 mg/dL. Evaluation of the rate of rise may shed further light on the
need for intervention.
Figure 3
Shows a week of HD IL-2 administration with typical evolution of daily serum BUN,
creatinine, potassium and bicarbonate values. In this patient the 1st and 2nd doses on day 3 are
held. Spontaneous improvement occurs with conclusion of dosing on day 5.
There is enhanced concern for mRCC patients, due to the presence of only one kidney in many
patients, and very rare cases from years ago in which patients suffered permanent renal damage. In
patients with anuria and only one kidney, ureteral obstruction should be considered and ruled out.
Dialysis is not indicated during treatment with HD IL-2. Discontinuing NSAIDS or nephrotoxic
antibiotics when the creatinine is above 3.0 mg/dL is also prudent. The use of nephrotoxic contrast
agents for imaging studies in patients receiving HD IL-2 should be not be prescribed as severe
kidney damage may ensue.
Examples
Center A - whose approach is to maintain blood pressure using relatively high volumes of fluid,
both as maintenance and as boluses for hypotension, will hold doses of IL-2 for oliguria of less than
80-160 ml/8 hour, and give furosemide. Most centers do not utilize diuretics except on an as needed
basis, since furosemide is only likely to be effective if given more than 4 hours after an IL-2 dose. If
there is no diuresis, then IL-2 doses will be delayed.
Center B - who uses vasopressors and smaller volumes of fluids, will monitor 24 hour urine output
and requires at least 100 ml/shift. If there is no improved output with holding a dose of IL-2 or if
there is steeply rising creatinine, then another IL-2 dose will be held until the output is increased.
Fluids will be given with vasopressors to attempt to improve output.
Center C - who uses a combination of fluids and vasopressors, also starts renal doses of dopamine
from the beginning of treatment. However, a prospective randomized trial compared prophylactic
use of low dose dopamine versus initiation of dopamine in response to oliguria, and found no benefit
to prophylactic use [47]. Therefore, the efficacy of prophylactic renal dose dopamine is not
confirmed. Dopamine may induce tachycardia which may prompt the holding of the next dose of IL2.
Metabolic acidosis
Hypocarbia occurs for a multitude of reasons during HD IL-2 treatment: pulmonary injury, renal
dysfunction, diarrhea, hypotension with high vasopressor levels resulting in poor tissue perfusion or
dilution, due to the administration of non-bicarbonate containing fluids. Bicarbonate
supplementation of IV fluids is recommended for serum bicarbonate levels of 19 mmol/L or an
absolute drop of 4 mmol/L from baseline. If the serum bicarbonate remains < 18 mmol/L despite
replacement, IL-2 should be held or stopped and bolus bicarbonate infusions administered. Low
sodium bicarbonate has been associated with refractoriness to vasopressors which further decreases
tissue perfusion, thus worsening the acidosis. It is important to replace the bicarbonate preemptively
in order to avoid this circumstance. Some centers use lactated ringers solution for maintenance
fluids and note their patients do not experience low serum bicarbonate levels. Most others utilize
saline for fluid support and give replacement boluses of bicarbonate as needed. Whatever strategy is
chosen it is critical not to fall behind in patients at greater risk.
Nausea/vomiting
Nausea/vomiting does not occur with all patients, but most centers prescribe scheduled prophylactic
anti-emetics as well as "as needed" orders. However, some patients require intensive anti-nausea
medication. The drugs preferred are ondansetron and granisetron, but some centers use
prochlorperazine as initial treatment, only advancing to 5-HT3 antagonists as necessary. Patients
who become symptomatic may benefit from conversion of oral medications to the intravenous route.
Mucositis
Mucositis does occur, but is not a problem for every patient. Therefore, it is managed on an as
needed basis, with local medications such as non-alcohol containing mouthwash and toothpastes.
Symptomatic mucositis may worsen upon discharge and may require additional management advice.
Diarrhea
Diarrhea can be minimal or extensive and varies from patient to patient. It is due to a combination of
effects such as oral antibiotics, bowel edema from capillary leak syndrome, and other cytokine
effects. It may be less of a problem than originally described perhaps due to continuous
administration of 5HT antagonists. Diarrhea can complicate IL-2 administration due to fluid loss,
electrolyte loss, local discomfort, inflammation, and even infection. Some centers postpone the night
dose of IL-2 until the next morning, when diarrhea is severe to allow recovery until the next
morning. Some centers convert oral antibiotics to IV, or switch to a single daily dose of vancomycin
to reduce the possibility or impact of diarrhea.
Peripheral edema and weight gain
Edema is a consequence of the capillary leak syndrome and fluid infusion, and in general causes
discomfort but is not serious. Administration of fluids should result in a minimum 1-2 lb per day
weight gain. Falling behind in fluid replacement may result in administering more fluid boluses,
problems with oliguria and increased creatinine, and high doses of vasopressors ultimately leading
to early cessation of IL-2 dosing. (Figure 4) Careful attention to daily weights and the rate of
increase is important. After stopping IL-2, many centers choose to initiate diuresis prior to
discharge, and may target achieving a weight that is within 5 pounds of admission. In general,
diuretics are not effective until about 6-8 hours after the last dose of IL-2 and the cyclical effects of
that dose begin to wane. If peripheral edema is present when the patient is otherwise ready for
discharge, several centers send patients home with a prescription for diuretics, but others do not,
advising the patient that diuresis will occur on its own. Mostly, this is a comfort issue, and patients
who are very uncomfortable should receive a prescription for diuretics, usually 20 to 40 mg of
furosemide depending on renal function, upon discharge with instructions to take until edema is
gone or weight returns to the immediate pre-admission level.
Figure 4
Plots weight (actual and ideal curve), fluid support (IV rate and boluses) during a cycle of HD
IL-2. As the week progresses, weight gain falls behind ideal and increasing fluid and bolus support
is necessary. Finally, vasopressor support is added before the final dose is administered.
Central nervous system neurotoxicity
All centers agree that this is a serious toxicity and one of the most difficult to anticipate. In
particular, it is a toxicity that can worsen in the absence of additional IL-2 treatment, so it is
important to identify early and withhold IL-2 therapy until its course can be established. Mild
neurotoxicity, such as restlessness or insomnia, once treated with benzodiazepines, should not cause
interruption of treatment with HD IL-2. Insomnia may be due to hospitalization and immobility or
from IL-2, and appropriate medication should be considered. Severe neurotoxicity is a criterion for
stopping IL-2 permanently. The progressive development of personality changes, hostility,
confusion, disorientation, hallucinations, are criteria for stopping that cycle of IL-2 and may require
intervention with anti-psychotic medications. Although generally occurring later in a cycle, gradual
decay does not always occur, and an additional dose may cause a change from agitation to
psychosis. Patients need to remain in the hospital until full recovery. Patients can be discharged on
benzodiazepines for several days if their toxicity is limited to irritability. The most important
management of CNS toxicity is continued reassurance and occasionally benzodiazepines or
haloperidol can be considered.
Peripheral neuropathy
Peripheral neuropathy is uncommon but can be quite debilitating particularly in the upper
extremities and may limit IL-2 dosing. This is due to an entrapment/compression syndrome in the
wrist or forearm, associated with edema [48]. Pain medications (usually codeine or oxycodone) or
medications more specific for neuropathy (gabapentin) may be helpful.
Cutaneous toxicity
Macular rash, redness and dry skin are common during IL-2 treatment, and progress as the week of
treatment continues. All centers provide topical medications during treatment such as emollients,
non-alcohol containing lotions, or non-steroid containing lotions or creams. Skin toxicity is
particularly noticeable in patients with fair skin, and generalized exfoliation and peeling of hands
and feet can occur, often after patients are discharged from the hospital. Lotions and emollients
should be started at or before the first sign of erythema.
Pruritus is not directly related to the degree of exfoliation. A small study has shown that pruritus is
not related to the eosinophilia that sometimes develops with HD IL-2 administration. Pruritus may
be cytokine mediated, as has been shown in cutaneous T-cell leukemia in which T-cells infiltrate the
skin, or due to hyperbilirubinemia (49). Although antihistamines are used for IL-2 induced pruritus,
one study has reported, and anecdotal reports have suggested, that gabapentin has a major beneficial
effect on pruritus [49]. Itch nerve fibers are pain fibers and gabapentin is effective in peripheral
neuropathy. If the pruritus is cytokine mediated, and reflects irritation of peripheral nerves, then
gabapentin would be expected to be beneficial. In severe cases opioids may be beneficial as the pain
fiber-mediated itch may respond to central acting agents. In patients where the opiates administered
for rigors are suspected as the cause, naltrexone may be used to treat the itching. Pruritus is not
dose-dependent. It may not be resolved in one week if the patient returns for the second cycle of IL2 treatment, and may be criteria for a delay. Skin management is an important part of discharge
planning.
Electrolyte abnormalities
A variety of electrolyte abnormalities are noted, including hypomagnesemia, hypocalcemia,
hypokalemia, hypophosphatemia and hyponatremia. These will progressively worsen during the
treatment and require careful correction (Figure 3). Most centers correct the magnesium and
potassium, and monitor the others. Often the serum calcium is normal after correcting for
hypoalbuminemia.
Hematologic toxicity
Acute changes in the cellular elements of the blood are expected and may be dramatic (Figure 5).
Thrombocytopenia is a common toxicity of HD IL-2 therapy. However, it rapidly reverses once IL-2
is discontinued and does not require intervention in most cases. Patients with mM who have
received prior chemotherapy are at risk for leukopenia during IL-2 therapy. It is not yet clear if
mRCC patients who have previously received anti-VEGF TKIs are at risk of leukopenia.
Figure 5
A logarithmic plot of blood lymphocyte, eosinophil, platelet and granulocyte absolute counts
and hemoglobin during a cycle of HD IL-2 administration. Platelet and lymphocyte counts fall
rapidly to very low levels. Eosinophils progressively rise during administration. After cessation of
treatment, platelets and lymphocytes quickly return to normal and often rebound to 2-5 times their
baseline levels. Eosinophilia may persist for weeks.
One group studied the bone marrows of IL-2 patients who developed thrombocytopenia and found
normal numbers and morphology of megakaryocytes. They attributed the thrombocytopenia to
sequestration in the spleen due to IL-2-induced splenomegaly (JPD, personal observation).
Lymphocytes similarly disappear within hours after the first dose, probably due to margination and
diapedesis into the tissues. Coagulation abnormalities have also been reported. Fibrinogen and ddimers were normal, thus arguing against consumption or microthrombi and suggesting impaired
hepatic synthesis [50]. Coagulation abnormalities and other hematologic toxicities rapidly reverse
with discontinuation of IL-2 and do not require altered dosing of IL-2. Anemia can occur but rarely
are transfusions required. In fact, if patients become significantly anemic during IL-2 administration,
other causes, such as hemorrhage, should be sought.
Hepatic enzyme and function abnormalities
The most frequent abnormalities noted are low albumin (both from capillary leak and decreased
synthesis), mild coagulopathy, hyperbilirubinemia, and less commonly hepatic enzyme elevations
[51],[52]. The bilirubin may rise to approach 10 mg/dL and the albumin drop to 2 gr/dL or less.
These will reverse once IL-2 is discontinued. Some sites discontinue acetaminophen if the bilirubin
becomes high, most do not. There does not appear to be a threshold for bilirubin abnormalities for
holding IL-2 or delaying IL-2. Elevation of hepatic enzymes does cause some concern when the
value is 5-10 fold above normal and some centers hold IL-2 for increases of this magnitude.
Criteria for holding or stopping HD IL-2
The main criteria used for holding and/or stopping IL-2 treatment are summarized in Table 3. The
severity of adverse events associated with bolus IL-2 peaks 4-6 hours after a dose and most
interventions will be employed at that time. It is critical to re-evaluate the patient before receiving
each dose to make sure that many of these events are improving or have subsided at that time.
Holding a dose of IL-2 is the preferred management of prolonged toxicity from a previous dose.
There are no individual dose reductions. If a toxicity occurs early in the cycle and returns to near
baseline, such as resolution of elevated heart rate or low blood pressure, then treatment can resume.
However, toxicity is cumulative over 5 days, both in extent and duration. In addition, toxicities
become increasingly refractory to treatment. Thus, later in the week, more intensive or sustained
toxicities become reasons to stop that cycle of IL-2. Recommendations for delaying, withholding or
stopping IL-2 doses have evolved from experience and are outlined below and in Table 3.
Table 3
Criteria for holding and stopping IL2 #
System
Relative criteria
Absolute criteria
Sinus tachycardia > 130 BPM*
ECG indications of ischemia
Atrial fibrillation
Cardiovascular
Sinus tachycardia 100-130 BPM* Supraventricular tachycardia
Ventricular arrhythmias**
Elevated CKB-MB isoenzyme of troponin
levels
Dermatologic
Moist desquamation
Diarrhea, 1000 ml/shift
Gastrointestinal
#
Hemodynamic *
Hemorrhagic
Neurologic
Vomiting not responsive to medication
Ileus/abdominal distention
Severe abdominal distention affecting
breathing
Bilirubin > 7 mg/dL
Severe, unrelenting abdominal pain
Maximum Phenylephrine 1-1.5
mcg/kg/min
Maximum Phenylephrine 1.5-2.0 mcg/kg/min
Minimum Phenylephrine > 0.5
mcg/kg/min
Minimum Phenylephrine > 0.8 mcg/kg/min
Sputum, emesis, or stool hemepositive
Frank blood in sputum, emesis, or stool
Platelets 30,000-50,000/mm3
Platelets < 30,000 mm3
Infectious
Musculoskeletal
Diarrhea 1000 ml/shift x 2
Strong clinical suspicion or documented
Weight gain > 15%
Extreme tightness
Extreme paresthesias
Vivid dreams
Hallucinations
Persistent crying
Mild anxiety
Mental status changes not reversible in 2
hours
System
Relative criteria
Absolute criteria
Unable to subtract serial "7 s" or spell
"WORLD" backward
Disorientation
Resting shortness of breath
Pulmonary
Renal
> 4 L O2 by nasal cannula or 40% by mask to
maintain ≥ 95% O2 saturation
3- 4 L O2 by nasal cannula for O2
Intubation
saturation ≥ 95%
Rales 1/3 up chest
Moist rales ½ up chest
Urine output 80-160 ml/shift
Urine < 80 ml/shift
Creatinine 2.5-2.9 mg/dL
Creatinine ≥ 3 mg/dL
HCO3 ≤ 18 meq/dL
Abbreviations: BPM, beats per minute; ECG, electrocardiogram.
*Persistent at the time of dosing after correcting hypotension, fever, and tachycardia and
discontinuing dopamine.
**Including premature ventricular contractions, bigeminy, and tachycardia.
#
In order to maintain acceptable BP and pulse criteria.
*Phenylephrine Max is during the interval, Min at the time of dosing.
#The above criteria should be assessed at the scheduled time of next dose after aggressive measures
to correct toxicity have been undertaken.
If ≤ 3 relative criteria, delay dosing, continue corrective measures and administer another dose if
recovered in < 24 hours.
If >3 relative criteria or an absolute criteria are observed stop IL-2 for the current cycle.
Cardiac
Holding
Sinus tachycardia is the norm after IL-2, but this should return to a pre-defined baseline before
administering further doses of IL-2. If the heart rate remains above 100-120 beats per minute after
correcting hypotension in an afebrile patient, when a dose is due, that dose should be delayed or
skipped.
Stopping
Sustained rapid (>130-140/min) supraventricular tachycardia or rapid atrial fibrillation will require
intervention, and stopping of IL-2, at least for the current cycle. If the supraventricular arrhythmia
can be converted to NSR quickly or the heart rate and blood pressure managed despite atrial
fibrillation, then consideration could be given to resuming IL-2 treatment. Once treated, IL-2 may be
administered in a subsequent cycle. Ventricular tachycardia or evidence of ischemic myocardial
damage are indications for permanently stopping IL-2 treatment. A diagnosis of myocarditis should
prompt discontinuation of that cycle of IL-2, but if LVEF returns to baseline, patients may
cautiously proceed with additional cycles of HD IL-2, usually without recurrence of this side effect.
Hypotension
Holding
IL-2 dosing should be delayed until hypotension recovers from the previous dose and the
vasopressor level (if applicable) is at a baseline established for dosing. If hypotension requires
additional fluid boluses then an assessment of respiratory function will help determine when the
next dose can be administered. If high doses of phenylephrine continue to be required, some patients
will respond to replacing phenylephrine with norepinephrine at low doses (prefer 2-4 mcg/kg/min
but may titrate up to 10 mcg/kg/min for short periods of time). If high-doses of vasopressors are
needed, IL-2 should be discontinued.
Stopping
The degree and duration of significant hypotension progresses during the week, and thus may
require more fluid or higher doses of vasopressors to maintain adequate blood pressure. When
hypotension requires maximum doses of vasopressors or a change to alternate vasopressors, such
norepinephrine, IL-2 should be stopped. IL-2 should also be stopped if fluid overload precludes
using fluids for maintaining blood pressure, as pulmonary reserve may be compromised.
Neurologic
Holding
Personality changes can be subtle, and it may be difficult to distinguish when they are the result of
IL-2 or from other causes. However, if staff or family observe a change in personality, exhibition of
agitation or emotional lability, IL-2 neurotoxicity must be considered. Improvement of mild
neuropsychiatric complications after drug therapy or after delay of a dose of IL-2 is a sign to then
continue dosing.
Stopping
As a precipitous decline may occur with additional IL-2 doses, lack of improvement with specific
therapy and passage of time warrants stopping therapy. The progression of personality changes or
agitation to extreme emotional lability, crying, aggressiveness, disorientation, or hallucinations are
absolute criteria for stopping IL-2. Such symptoms of neurotoxicity may require medication and
continued hospitalization until resolution. Rarely peripheral compression neuropathy or vasospasm
occurs, resulting in finger pain or paresthesias poorly responsive to medication which may also
require stopping IL-2. This is more common during second or subsequent courses of therapy.
Pulmonary
Holding
Dyspnea and hypoxia reflect capillary leak and can lead to a requirement for oxygen to maintain an
oxygen saturation of 95%. Oxygenation should be carefully monitored and maintained. Patients may
develop tachypnea and rales. Tachypnea may also result from acidosis or fever which should also be
corrected. Delaying IL-2 administration will allow diuresis spontaneously or with diuretics, and
after improvement, it may be possible to administer additional IL-2. Patients may develop wheezing
despite nebulizers and this may reflect capillary leak or bronchospasm or both. Careful diagnosis
and aggressive correction of pulmonary symptoms should occur quickly. The severity will influence
the decision to delay or discontinue IL-2 therapy.
Stopping
Patients with dyspnea or hypoxia requiring more than 4 liters of oxygen to maintain saturation of
95% or who are clearly fluid overloaded are at risk for continuing IL-2. Intubation should not be
necessary with current guidelines, but is an absolute indication for stopping IL-2.
Oliguria/creatinine
Holding
Pre-established criteria at each center are used to determine if urine output and serum creatinine are
adequate to administer another dose. Some centers require urine output of 30 ml/hour, others 80-160
ml/8 hour shift. Some centers delay a dose of IL-2 when urine output has fallen, and resume IL-2
when urine output is evident. Some centers will only delay a dose if oliguria is accompanied by
other signs of significant toxicity, such as fluid overload that does not allow further fluid
replacement. Elevated serum creatinine concentration alone is usually not a reason for delaying a
dose of IL-2, since it is primarily a reflection of hypotension, capillary leak, and/or oliguria.
However, many centers set a threshold level for serum creatinine, and will stop IL-2 treatment if the
level rises above 3 to 5 mg/dL. Dialysis is not necessary, as renal function returns upon cessation of
IL-2 administration.
Stopping
Each center will set its criteria for tolerability of oliguria and/or serum creatinine level with which to
hold or stop IL-2. This is related to the degree of capillary leak, the rate of rise of serum creatinine,
the degree of oliguria, and responsiveness to holding a dose of IL-2.
Diarrhea
Holding
If diarrhea becomes very frequent, such as 5-6 movements/day of any volume, most centers would
delay IL-2 therapy to allow some recovery. If diarrhea improves with delaying doses, IL-2 may
continue, but if as a consequence of the diarrhea, the patient develops local pain and irritation and
fluid loss and electrolyte imbalance are apparent holding another dose of IL-2 is prudent. If there is
concern about infection, treatment may have to be discontinued. Electrolytes should be replaced as
needed, particularly bicarbonate, prior to resuming IL-2. Patients who have had prior treatment with
ipilimumab and develop diarrhea while on high dose IL-2 should be evaluated for inflammatory
colitis.
Stopping
Rarely, continued large volume or frequent diarrhea despite medical intervention requires stopping
IL-2. Electrolyte loss may not be compensated by replacement and due to the depressed renal
function overshoots of potassium are to be avoided. If there is voluminous diarrhea, examination for
hemorrhagic diarrhea or C. difficile toxin should be obtained. This is rare, but must be ruled out in
this setting.
Metabolic acidosis
Holding
This can be a result of diarrheal losses of bicarbonate or lactic acidosis due to tissue hypoperfusion.
If replacement controls the level of serum HCO3, then IL-2 can be continued. Utilization of lactated
Ringer's instead of half normal saline for maintainance fluid may prevent low serum bicarbonate
levels. The occurrence of a serum HCO3 level of < 18 meq/dL is a worrisome sign and must be
promptly addressed. If it does not quickly respond to bicarbonate replacement then an alternative
source of acid production, such as bowel ischemia, should be considered and sought. For centers
that use Ringers Lactate as maintenance intravenous fluids, the need for bicarbonate boluses has
largely been eliminated, as significant acidosis has not been observed.
Stopping
Serum bicarbonate of < 18 meq/dL unresponsive to replacement therapy is reason for stopping IL-2.
Hematologic
Holding
Changes in blood counts are usually mild and not a reason to hold IL-2. Platelet counts have been
seen as low as in the 20,000/mm3 range, but rapidly recover after stopping IL-2. Some centers will
transfuse, however, and stop on the basis of thrombocytopenia, if more than 10 doses have been
administered.
Stopping
There is almost never a reduction in hemoglobin sufficient to transfuse, so if that occurs, a search for
additional causes should be made. Examples may include bleeding and in one case, pure red cell
aplasia was noted in the marrow immediately following IL-2 therapy (JPD, personal
communication).
Infection
Stopping
Any documented gastrointestinal or central line infection or suspected sepsis is a criterion to stop
IL2. Central venous catheters should be promptly removed as line infection can quickly proceed to
septicemia particularly if Staphylococcus aureus is the cause.
Cutaneous
Delay cycle
If severe cutaneous toxicity does not resolve mid-cycle, a delay in the second week is sometimes
necessary.
Stopping
Rarely pruritus or cutaneous toxicity can accelerate, particularly during the second cycle of IL-2
treatment, and the sensation may become intolerable, despite treatment. This may be a criterion for
stopping due to patient discomfort.
Malaise/intolerance
Stopping
Patients may state that they cannot tolerate more treatment and most IL-2 oncologists will stop IL-2
in the face of extreme agitation or when patients do not wish to continue.
Other
Clearly if there are issues that require transfer of a patient to an ICU because of decompensation
then IL-2 should be discontinued at that time. This recommendation does not apply to patients
electively treated in an ICU setting from the very beginning or when routine transfer to an ICU is
necessary for the use of vasopressors.
Discharge management
Discharge planning should continue throughout the hospitalization, to familiarize the patient and
home caregivers with routines and expectations during the first few days home. Once IL-2 is
discontinued, patients recover very quickly from its effects despite the cumulative toxicity
experienced during the cycle. Usually by 12 hours after the last dose of IL-2 patients are anxious to
leave the hospital and return home. If they are still requiring vasopressors, they must be weaned off
and blood pressure must be stable while they ambulate with assistance. They should be prepared to
sleep for several hours upon returning home since they will still be experiencing significant fatigue.
Most sites advise patients not to drive or use dangerous equipment for several days. Vivid dreams
may occur during the first several nights home which may be frightening. Sleep medication may be
needed short-term.
The serum creatinine usually levels off or begins to fall by the time of discharge, but if it is still
elevated, it usually will normalize within the next several days. Some centers prefer to recheck BUN
and creatinine after discharge, but experience has shown that this is unnecessary.
At discharge, patients will still have fluid overload, mostly peripheral, and some centers provide a
prescription for diuretics to be used as needed, particularly if diuretics were necessary in the hospital
after IL-2 cessation. Rarely, patients have fluid shifts from the periphery into the pulmonary
capillary bed, and develop late dyspnea requiring diuresis. Patients receiving diuretics should be
instructed not to take them until they arrive at home, in order to minimize risk of emergency stops
on the way home from the hospital.
Patients who have pre-existing hypertension will need to resume their medications during the week
between cycles, usually starting 48 hours after discharge, and they will have to stop these
medications within 48 hours prior to their next admission for IL-2. If patients are planning further
IL-2 treatment they should not re-start beta-blockers.
For those patients who experience cutaneous manifestations, the erythematous rash may evolve into
extensive peeling of the epidermis after hospital discharge, particularly involving the palms and
soles. Pruritus may worsen after discharge, and creams should be used liberally as well as increasing
doses of gabapentin and potentially opioids. Uncommonly, skin excoriation as a result of pruritus
may delay the second cycle of IL-2, if there are open lesions and severe redness.
Hypothyroidism, sometimes preceded by an episode of hyperthyroidism, can occur weeks or months
after IL-2 therapy and thyroid function should be monitored during regular follow-up visits [53][55]. If a patient returns for IL-2 therapy and is severely hypothyroid, hormone replacement should
be initiated. IL-2 should be delayed until a euthyroid state is achieved on a stable replacement dose.
Patients who are used to aerobic physical activity will note that their stamina and lung capacity are
less, immediately following IL-2. This will improve as they recondition. These are delayed effects
of capillary leak and cytokines on the cardiopulmonary systems that spontaneously resolve.
The patient should be warned that iodinated contrast media used in radiographic studies have caused
skin and systemic reactions in patients who have received prior HD IL-2 [56]. These reactions may
be intense and mimic the side effects of IL-2, including oliguria and elevation in creatinine levels.
Hence, using iodinated contrast agents immediately prior to retreatment with IL-2 should be
avoided.
Follow-up phone contact is important in the first one to two weeks following IL-2 treatment,
followed by regular follow-up visits with scans to assess disease status. Follow-up scans are usually
obtained 6-12 weeks after a full course of IL-2 therapy is completed to assure that there is no rapid
growth of disease. Sometimes this scan will in fact show an early response, or small growth with
subsequent response at the next scan. A second scan at 12-16 weeks will confirm whether benefit
has occurred. However, there have been patients who have demonstrated continued response scan by
scan over the course of a year, and others who were stable for 6 months, and then showed tumor
regression. Other anecdotal reports describe patients who have been stable and had residual,
previously biopsied disease resected, which was found to be only scar tissue. Although the natural
course of response after IL-2 is not well defined, it may be important to allow sufficient time for
immunotherapy to work before changing treatment approaches such as IL-2, as other forms of
immunotherapy has been associated with delayed kinetics of tumor regression. Additionally for
patients who remain stable after IL-2 therapy, this appears to be of clinical benefit and such patients
may be monitored or retreated [9],[10],[13].
Relapse of disease in patients that have previously responded to IL-2 generally raises the question of
retreatment with IL-2. However, multiple factors will need to be considered, such as the amount of
prior IL-2 received, the intensity of side effects experienced, and other treatment options. In
addition, it should be noted that retreatment with IL-2 alone in this setting may be less effective
[57].
Establishing HD IL2/immunotherapy centers
Clinical requirements
All personnel need to have specialized training in managing HD IL-2 patients. Usual maneuvers to
treat patients with cytokine-induced systemic responses, such as sepsis, are managed very
differently than HD IL-2 patients. Anticipation of the expected side effects, and rapid appropriate
correction are central to management of these patients. Treating a minimum number of patients per
year is important, as quality depends upon familiarity and repetition.
Nursing requirements
The optimal scenario is that there is sufficient nursing staff to have a reduced patient ratio on all
shifts such as 1 nurse to 2-3 patients. The lower nurse to patient ratio of 1-2 may be necessary
during day 3, 4, or 5 of IL-2 treatment when the patient is experiencing more varied and intense IL-2
side effects. This may be less critical as the nursing staff becomes more familiar with the
management of HD IL-2 patients. It is preferable to have cardiac monitoring, with BP, HR, and
oxygen saturation panels available for regular use. Intensive in-service training should be provided
for all shifts and for new staff as needed. Patient comfort and education are important nursing goals
[58].
Physician commitment
It is preferable that more than one physician be trained and accept responsibility for patient
management. In some centers a group of only medical oncologists or oncologic surgeons are
responsible and in others centers an oncologist will share management with cardiology and
pulmonary staff, either on the oncology unit or in the ICU. Others utilize specially trained
hospitalists or even oncology hospitalists for IL-2 management, particularly at night. Nurse
practitioners or physician assistants have also maintained coverage in some centers with backup
support from a covering medical oncologist.
Immunotherapy coordinator
This person(s) is usually a nurse who is responsible for organizing the pre-screening of patients for
IL-2 eligibility, as well as obtaining insurance approval. In most centers, this individual is also
involved in discharge management and follow-up for IL-2 patients and is fully aware of the special
needs of their management and follow-up.
Administrative issues
Prior to establishing the HD IL-2 treatment program, there must be an evaluation of institutional
policies regarding cardiac monitoring and use of vasopressors on a regular oncology unit, versus a
requirement for ICU care. Management of HD IL-2 is much more akin to a surgical procedure
where the patient is admitted with an expectation of a standard length of admission and utilization of
a predictable amount of hospital resource with a discharge home of a convalescing patient. If IL-2 is
to be given on a regular unit, an assessment of what type of nursing training will be required for
cardiac monitoring, frequent vital signs, and vasopressor management will need to be made.
Attention to integrating clinical assessment and pharmacy preparation of the drug is also important
to avoid wasting drug or inadvertent administration to a patient experiencing a significant toxicity.
Based on these issues, the following two key questions will need to be addressed: Where in the
hospital will HD IL2 be administered? Who will be responsible for patient management?
Regardless of the setting, low nurse/patient ratios, experience in managing complex acutely ill
patients and consistent practice in these settings is critical. HD IL-2 specific training for all
personnel is essential to success. Hospital policies and availability of resources often determines
where HD IL-2 is administered.
ICU setting
Some centers only use vasopressors in an ICU. Nursing staff levels may also be an issue for nonICU management in some institutions. ICU nurses must be specifically trained in management of
IL-2 patients, as HD IL-2 management decisions are often counter intuitive to standard ICU
practice. Staff should comply with chemotherapy certification if hospital policy dictates, but it is not
necessary. In the ICU, there must be clear delineation of which physician team will have primary
responsibility for the patients. Ideally, it should be the HD IL-2 team, rather than the ICU
physicians.
Hematopoietic Stem Cell Transplant/HD IL-2 Unit: A high intensity oncology unit is available at
some centers. IL-2 treatment and stem cell transplant both require intensive nursing, monitoring and
management. This is a natural setting for HD IL-2.
Inpatient oncology unit
Experienced high volume centers often administer all HD IL-2 on a standard oncology unit
equipped for cardiac monitoring. Alternatively, sites may start treatment on an oncology unit and
transfer to ICU when it is necessary to monitor and administer vasopressors. If transfer to an ICU
does occur, the same medical team should have primary responsibility for the care of the patient.
All these facets of care should be clearly defined and agreed upon by all parties before training,
instruction, and treatment begins.
Financial/Billing issues
There must be an education of medical records and billing staff to allow optimal documentation for
coding and billing for the level of intensity of HD IL-2 administration. They must be cognizant of
the dedicated DRG and CPT codes for IL-2 administration. A training session can be provided for
instruction in recognizing the specific terms and converting to specific coding for IL-2.
Medical and nursing personnel who are documenting care and management of these patients need to
be trained in carefully documenting the clinical issues and the severity of illness during IL-2
administration.
Some institutions will require a cost analysis prior to initiating and supporting an IL-2 program.
Conclusions
High dose interleukin-2 remains an important component of the therapeutic armamentarium for
patients with metastatic renal cell cancer and metastatic melanoma. A subset of these patients
continue to achieve a consistent durable complete response that can last for decades. The authors
agree that peri-treatment mortality can be reduced to less than 1% when guidelines are diligently
followed. High priority research includes an exploration of combination therapy wherein IL-2 is
used with other immunotherapy agents, stereotactic radiation, or new targeted therapeutics being
developed for these diseases [44],[59]. Another high priority is the identification and validation of
predictive biomarkers to better select potential responders prior to treatment. The education of more
physicians in how to administer HD IL-2 and manage patients on treatment can increase the number
of patients who might benefit from the therapy. This Best Practices manuscript has been developed
to further enhance guidance for administration of HD IL-2 by surveying the experience of more than
20 experts with years of experience in its utilization.
Authors' contributions
All authors contributed to the manuscript writing and gave final approval to the manuscript. HLK,
DJS, AAT, SSA, MBA and JNL participated in a 2 day roundtable discussion of managing patients
receiving HD IL-2 with the intention of creating best practices. JPD and JNL assembled the
information from the conference into a draft manuscript that was reviewed and revised by all
authors.
Additional file
Abbreviations
HD:
High dose
CR:
Complete response
IL-2:
Interleukin-2
mRCC:
Metastatic Renal Cell Carcinoma
mM:
Metastatic melanoma
LAK:
Lymphokine activated killer
LVEF:
Left ventricular ejection fraction
TNF-α:
Tumor Necrosis Factor Alpha
BUN:
Blood urea nitrogen
NCI:
National Cancer Institute
IU:
International units
IU/kg:
International units/kilogram
CWG:
Cytokine Working Group
ICU:
Intensive Care Unit
ECOG:
Eastern Cooperative Oncology Group
K:
Karnofsky
PS:
Performance status
CAD:
Coronary artery disease
VEGF:
Vascular endothelial growth factor
TKI:
Tyrosine kinase inhibitor
EKG:
Electrocardiogram
PRN:
As needed
NSAIDS:
Non-steroidal anti-inflammatory drugs
mg/dL:
Milligram/deciliter
SIRS:
Systemic inflammatory response syndrome
mmHg:
Millimeter of mercury
BP:
Blood pressure
mcg/kg/min:
Microgram/kilogram/minute
LR:
Lactated ringers
HR:
Heart rate
PVCs:
Premature ventricular contractions
SVT:
Supraventricular tachycardia
mmol/L:
Millimole/liter
5-HT3:
5-hydroxytryptamine
lb:
Pound
mg:
Milligram
CNS:
Central nervous system
g/dL:
Gram/deciliter
LVEF:
Left ventricular ejection fraction
HCO3:
Bicarbonate
mm:
Millimeter
DRG:
Diagnosis related group
CPT:
Current procedural terminology
VEGFR:
Vascular endothelial growth factor receptor
Declarations
Acknowledgements
The authors wish to thank the following for their contributions: Brendan Curti for providing the
Providence Hospital HD IL-2 orders as the basis for the standing orders in this paper. Maude
Becker, Nancy Moldawer, Jill Titze, Krista Rubin, Kristan Rheinheimer and Lisa Eifler participated
in the conference and provided nursing perspective for this paper. Michael Wong, Leslie
Oleksowitz, Robert Figlin, David McDermott, Michael Morse, Gregory Daniels, Mayer Fishman,
Sapna Patel, Joe Clark, Kim Margolin, Michael Lotze, William Sharfman, Mario Sznol and many
others for their insight in how they manage patients receiving HD IL-2. Sandra Aung, Michael
Holman, Nancy Gregory and Eric Hallowell for their editing assistance.
Electronic supplementary material
40425_2014_26_MOESM1_ESM.doc Additional file 1: Standing order example. (DOC 34 KB)
Below are the links to the authors’ original submitted files for images.
40425_2014_26_MOESM2_ESM.gif Authors’ original file for figure 1
40425_2014_26_MOESM3_ESM.gif Authors’ original file for figure 2
40425_2014_26_MOESM4_ESM.gif Authors’ original file for figure 3
40425_2014_26_MOESM5_ESM.gif Authors’ original file for figure 4
40425_2014_26_MOESM6_ESM.gif Authors’ original file for figure 5
Competing interests
The conference on which this manuscript was based was sponsored by Prometheus. HLK, DJS,
AAT, SSA and MBA were consultants for this conference. JNL is an employee of Prometheus
Laboratories Inc. JPD is a consultant and on the speaker's bureau for Prometheus.
Authors’ Affiliations
(1)
Associate Director, Cancer Research Foundation
(2)
Associate Director of Clinical Operations, Professor of Surgery, IU Simon Cancer Center
(3)
Chief Surgical Officer and Associate Director for Clinical Science, Professor of Surgery, Rutgers
Cancer Center Institute of New Jersey
(4)
Chief of Medical Oncology and Professor of Medicine, St. Luke's Cancer Center
(5)
Associate Professor of Medicine and Translational Science, University of Pittsburgh Cancer
Institute
(6)
Senior Medical Director, Prometheus Laboratories Inc
(7)
Deputy Director, Professor of Medicine, Georgetown-Lombardi Comprehensive Cancer Center
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Table of Contents
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Abstract
Introduction
Review: Where is high dose IL-2 management today?
Conclusions
Authors' contributions
Additional file
Declarations
References
Comments
Metrics
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